This PPG will investigate the cellular, molecular and immunological properties of the cell surface inhibitory receptor programmed death-1 (PD-1) and how it functions during chronic viral infection. It is now well established that T cell dysfunction is a cardinal feature of many chronic viral infections and this is most strikingly seen during HIV infection. Recent studies have shown that the PD-1 inhibitory pathway plays a critical role in modulating this functional exhaustion of virus specific T cells. This has now been documented in several animal models such as murine LCMV infection and SIV infection of non-human primates and, more importantly, in humans during persistent infection with HIV, HBV and HCV. In addition to a role in regulating chronic viral infections, there is growing evidence that PD-1 plays an important role in tumors, autoimmunity and transplantation. However, despite PD-1's clear importance in maintenance of a healthy state little is known about PD-1 signaling and gene expression at the molecular level. With this in mind, the specific goals of this PPG are: 1) To elucidate the mechanisms of PD-1 function, signaling, and gene expression in healthy and HIV infected individuals and in model systems; and 2) To identify novel pathways, targets, and reagents that may be used to modify PD-1 expression and signaling in the treatment of immunological disease and viral infection. To achieve the above goals, we have assembled an outstanding team of investigators who will participate in the following four projects and three cores in this PPG: Project 1, PD-1 expression and HIV specific T cell dysfunction; Project 2, Regulation of PD-1 gene expression; Project 3, PD-1 signaling in T cells during chronic viral infection; Project 4, Targeting the PD-1 signaling pathway to rescue HIV T cell dysfunction. Taken together, these studies should provide insight into the mechanisms by which PD-1 regulates chronic viral infection and provide targets for therapeutic treatment of HIV infection. This molecular understanding of PD-1 function and regulation should also have implications for the treatment of tumors and autoimmunity, and for increasing the success of transplantation.